Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism

Weiqi Hong, Fei Mo, Ziqi Zhang, Mengyuan Huang, Xiawei Wei, Weiqi Hong, Fei Mo, Ziqi Zhang, Mengyuan Huang, Xiawei Wei

Abstract

NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia-reperfusion injury, heart failure, Alzheimer's disease, and retinal degeneration.

Keywords: Alzheimer’s disease; aging; diabetes; nicotinamide adenine dinucleotide (NAD); nicotinamide mononucleotide (NMN); obesity.

Copyright © 2020 Hong, Mo, Zhang, Huang and Wei.

Figures

FIGURE 1
FIGURE 1
Biosynthetic pathways of NAD+ in mammalian cells includes de novo, Preiss–Handler, and salvage pathways, and the salvage pathway is the main source of NAD+. NAD, nicotinamide adenine dinucleotide; NA, nicotinic acid; NAPRT, nicotinic acid phosphoribosyltransferase; NAMN, nicotinic acid mononucleotide; NAAD, nicotinic acid adenine dinucleotide; NADS, NAD+ synthetase; NMNAT, nicotinamide/nicotinic acid mononucleotide adenylyltransferase; ACMS, 2-amino-3-carboxymuconate semialdehyde; QA, quinolinic acid; QPRT, quinolinate phosphoribosyltransferase; NAM, nicotinamide; NAMPT, nicotinamide phophoribosyltransferase; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase.
FIGURE 2
FIGURE 2
Hypothetic molecule mechanisms of NAD+ decreased with aging. Oxidative stress, DNA damage, and chronic inflammation are increased with aging, which results in accelerated NAD degradation via activation of CD38 and PARPs, or dysregulation of NAMPT. Finally, decreased levels of NAD+ lead to various metabolic and age-associated diseases.
FIGURE 3
FIGURE 3
Nicotinamide mononucleotide exerts pharmacological effects by increasing intracellular NAD+ levels. Extracellular NMN is cleavage by CD73, which yields NR that is incorporated into cells using equilibrative nucleoside transporters (ENTs). NMN is converted to NAD+, which produces beneficial effects on cell, including mitochondrial function, DNA repair, gene expression, anti-inflammation and cell survival.
FIGURE 4
FIGURE 4
Nicotinamide mononucleotide ameliorates various diseases by increasing NAD+ levels in human. NMN is a promising molecule for therapy of diverse diseases, including diabetes, obesity, ischemia–reperfusion injury, heart failure, Alzheimer’s disease, retinal degeneration, acute kidney injury, and so on.

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